The Food and Drug Administration (FDA) conducted an inspection of your firm, Craig General Hospital, located in Vinita, Oklahoma, on July 20-28, August 1, and August 26, 2008. During the inspection, the FDA investigator documented violations of Section 501(a)(2)(B) (21 U.S.C. 351) of the federal Food, Drug, and Cosmetic Act (the Act) and Title 21, Code of Federal Regulations (21 CFR) Parts 600-680. Listed below are certain serious violations that reveal problems with your firm's Good Manufacturing Practices (GMP).

At the close of the inspection, you were issued a Form FDA-483, Inspectional Observations, that listed a number of deviations which include, but are not limited to the following:

1. Your firm failed to maintain written standard operating procedures (SOPs) including all steps to be followed in the processing, compatibility testing, and storage of blood and blood components for transfusion purposes [21 CFR 606.100(b)]. For example:

A. On July 13, 2008, your employee collected a blood sample from out patient (b)(6) and (b)(7)(C) for a complete blood count (CBC). This employee requested that the outpatient return be wrist banded for a blood crossmatch. The employee then labeled the blood sample tube for patient (b)(6) and (b)(7)(C) with the blood bank recipient identification number ("R" number) for outpatient (b)(6) and (b)(7)(C). The employee failed to verify that the information on the request form matched the label on the blood sample tube. The employee performed a crossmatch using the blood sample from patient (b)(6) and (b)(7)(C) who was the wrong patient, instead of outpatient (b)(6) and (b)(7)(C). Patient (b)(6) and (b)(7)(C) was blood group A+ but outpatient (b)(6) and (b)(7)(C) was blood group 0+. Outpatient (b)(6) and (b)(7)(C) received by transfusion red blood cells that were A+ based on the crossmatches that used the blood sample from patient (b)(6) and (b)(7)(C). Because the SOPs were not followed by the employee, incompatible red blood cells were transfused into outpatient (b)(6) and (b)(7)(C) who later died from a hemolytic transfusion reaction. There were at least two lab techs working this shift to do the second review of the work preformed by this employee.

Although your firm's SOP on determining the compatibility by pre-transfusion testing of the recipient states that the request form and the sample label must be compared before testing can begin and if there is a discrepancy concerning the specimen, a new sample must be drawn, your employee failed to follow the SOP. In addition, the SOP for the transfusion services quality control states that two people must check the identification and record all steps involved with pre-transfusion testing and administering blood and blood components, such as patient's name, number, date, and phlebotomist's initials that should be on the sample tube. Again, this same employee failed to follow this SOP and have the work reviewed and verified by another employee before proceeding.

The SOP for blood returned to the blood bank states that blood discontinued due to possible transfusion reaction can be stored in the bottom of the blood bank refrigerator with previously issued blood units until no longer needed. However, the blood bank no longer has the same blood bank refrigerator. Instead, the Frigidaire refrigerator (used for a backup for the blood bank refrigerator) is where all the quarantined blood products are kept. This refrigerator also stores blood reagents, red blood cells for testing, and patient samples as well as quarantined unsuitable blood components. This refrigerator has no designated areas or a method to segregate all these products. The unit that was transfused into the wrong patient was still in the bottom of this refrigerator on August 1, 2008.

B. There are no written SOPs or the procedure is inadequate or incomplete. For example:

There are no written directions for receiving and storing platelets until the product is transfused. The blood bank receives the platelets but does not record the receiving temperature, the time received, and the integrity of the bag. Furthermore, the platelets are placed on a rocker for agitation and the room temperature is not required to be monitored and recorded.

There are no written directions for receiving, thawing, handling, and issuing Cryoprecipitate AHF. There are no directions for thawing this product that states no more than 15 minutes should be used for unthawing and that the temperature should be between 30-37 degrees C.

The SOP for single donor fresh frozen plasma (FFP) states that immediately before use, FFP should be unthawed with agitation in a water bath at temperatures between 30-37 degrees C. and the FFP can be stored unthawed under proper refrigeration for no more than 24 hours. However, the blood bank thaws the FFP in a tub of water without using a thermometer to monitor the temperature of the water. The product is only agitated when the employee unthawing the FFP checks to determine the stage of thawing. The SOP does not state the temperature for storage and there is no variance for the 24 hour expiration from the Center of Biologics for Evaluation and Research (CBER) on file.

There is no SOP for the storage of patient sample tubes after cross-matching. On Jul 13, 2008, after the blood bank was notified that patient (b)(6) and (b)(7)(C) had a possible transfusion reaction, your employee found the blood sample tube for patient (b)(6) and (b)(7)(C) identified with the "R" number of patient (b)(6) and (b)(7)(C) in the complete blood count (CBC) rack in the laboratory. Patient sample tubes stored in the laboratory refrigerator are only kept for seven days. The blood bank's practice is to store the patient sample tubes in the blood bank's reagent refrigerator after crossmatching a patient. Without an SOP, employees may misplace and/or discard the patient sample tubes.

2. Your employee failed to adequately provide for identification and handling of all test samples so that they are accurately related to a specific recipient [21 CFR 606.140(c)].

On July 13, 2008, the employee failed to properly handle patient blood samples resulting in the wrong sample tube being used to perform the crossmatch. Patient #3330998 was used mistakenly for crossmatching outpatient (b)(6) and (b)(7)(C) resulting in an incompatible red blood cell unit being transfused into patient (b)(6) and (b)(7)(C). Furthermore, this blood sample from patient (b)(6) and (b)(7)(C) identified with "R" number patient (b)(6) and (b)(7)(C) was later found in the CBC rack in the laboratory instead of the reagent refrigerator. This same tube without the "R" number for patient (b)(6) and (b)(7)(C) was then found at the workbench for compatibility testing for blood components.

3. Failure to calibrate equipment used in the compatibility testing, storage, and distribution of blood and blood components on a regularly scheduled basis as prescribed in the SOP Manual to assure that it performs in the manner for which it was designed [21 CFR 606.60(a)].

Your firm has not calibrated the thermometer used to calibrate the blood bank thermometers against a National Institute of Standards and Technology (NIST) traceable thermometer since December 29, 1992. In addition, the blood bank thermometers that are used to monitor the refrigerators used for storing blood components and reagents, and the thermometers used in monitoring the temperatures during compatibility testing, are not calibrated on an established written schedule.

4. Failure to maintain processing, storage and distribution, and general records [21 CFR 606.160(b)]. For example:

• No visual inspection of red blood cells during storage is recorded.

• No documentation of temperatures or visual inspection of blood components upon receipt.

• No documentation that the temperature of platelets are received at 20-24 degrees C and stored at this same temperature until distributed.

• No documentation that FFP is thawed at 30-37 degrees C.

• No documentation that Cryoprecipitate AHF is thawed between 30-37 degrees C for no more than 15 minutes.

• No documentation that the blood bank thermometers used for monitoring the storage temperatures of blood components and the compatibility testing have been calibrated against a thermometer traceable to a NIST standard at written specified intervals. In addition, there is no documentation that the thermometer used to calibrate the blood bank thermometers has been calibrated against a thermometer traceable to a NIST standard at written intervals.

The above identification of violations is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that all blood and blood components processed and issued by your blood bank are in compliance with the Act and the GMP regulations. You should take prompt action to correct these violations. Failure to correct these violations may result in administrative and/or regulatory action without further notice, including seizure and/or injunction.

We received your November 4, 2008 response to the FDA 483, Inspectional Observations, that the FDA investigator issued at the conclusion of the recent inspection of your firm. We have completed our review of your response and have determined that your response appears to be inadequate to address all the violations that FDA documented at your firm. Our evaluation follows and is numbered or labeled to correspond to the items as they appeared on the FDA-483 and in your response:

Item 1 A. 1,2,3. The response appears to be adequate to address the noted observation; however, 1A.3 states that the racks of the Frigidaire refrigerator are to be labeled with appropriate types, crossmatched units, and quarantined units, but it is unclear if the racks are labeled at all times or only when this refrigerator is used to store blood components because the blood bank refrigerator is not working properly.

Item 1 B. 2,3,5. The response appears to be inadequate. You have incorporated the directions for unthawing fresh frozen plasma (FFP) and Cryoprecipitate AHF (AHF) along with the monitoring of the temperature of the platelets on the rocker in the standard operating procedure (SOP) (b)(4) RECEIVING AND PROCESSING FOR BLOOD BANK". Your SOP addresses the receipt of product from (b)(4) but in step 5, you continue to give directions for the process of unthawing FFP and Cryoprecipitate AHF. Furthermore, under the platelet pheresis heading, step 2, you have directions for placing the platelets on the rocker and how to monitor the temperature. The process of thawing FFP and Cryoprecipitate AHF, along with monitoring the platelets, is a critical step in good manufacturing practices (GMP) to maintain the potency, safety, and purity of these products. Therefore, in order for your employee to easily identify these products and perform these processes, you should have a separate SOP that addresses the thawing of the FFP and Cryoprecipitate AHF, and the monitoring of the platelets.

You state that FFP should not be thawed longer than 15 minutes according to the FDA; however, it is the Cryoprecipitate AHF that is to be thawed for no more than 15 minutes at 30-37°C [21 CFR 606.122(n)(4)].

In addition, you state that FFP expires in 24 hours after being thawed. The Instruction Circular, 21 CFR 606.122(m)(3), has the directions to administer the plasma product within 6 hours after thawing. If you intend to label your FFP with the expiration time of 24 hours after thawing, you will have to request an alternative procedure (variance), 21 CFR 640.120, from the Center for Biologics Evaluation and Research (CBER).

Item 8. E,F,G. The response appears to be inadequate. You refer to the same SOP listed in Item 1 B. 2,3,5. However, as discussed above, these directions should be in the same SOP for the performance of the process of thawing FFP and AHF, as well as the monitoring of the platelets; not in the (b)(4) RECEIVING AND PROCESSING FOR BLOOD BANK"

Also, the SOPs for the plasma and cryoprecipitate thawing water bath system, thermometers, competency evaluation and quality assurance, donor unit inventory and ordering, and transfusion reaction were signed but did not have an effective date/revision date.

Your responses to the other items appear to be adequate; however, these can only be fully evaluated after implementation takes place.

We request that you notify this office, in writing, within fifteen (15) working days of the receipt of this letter of the specific steps you have taken to correct these violations, including examples of any documentation showing that corrections have been achieved. If you cannot complete all the corrections before you respond, please explain the reason for your delay and the date by which each item will be corrected and documented.

Please send your reply to the Food and Drug Administration, Attention: Carolyn A. Pinney, Compliance Officer, at the above letterhead address. If you have any questions regarding any issue in the letter, please contact Carolyn A. Pinney at (214) 253-5220.